Stabilized composition comprising antidementia medicament

ABSTRACT

The present invention provides a stable composition of an antidementia medicament. Specifically, it is a stabilized composition of an antidementia medicament comprising an antidementia medicament and an organic acid. As the organic acid, tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid, citric acid and the like are particularly preferable.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/JP99/01686 which has an Internationalfiling date of Mar. 31, 1999, which designated the United States ofAmerica.

FIELD OF INDUSTRIAL APPLICATION

The present invention relates to a stabilized composition of anantidementia medicament, especially, donepezil and also to a method ofstabilizing donepezil.

PRIOR ART

Along with the emergence of a recent social problem concerning care ofsenile dementia, remedies for the senile dementia have beenenergetically developed. Among these, donepezil has an acetylcholineesterase inhibitory effect and is highly evaluated for its usefulness asa remedy for slight to medium degree of Alzheimer's dementia. Becausedonepezil is a basic medicament, it is provided as a salt ofhydrochloric acid.

While, when medicaments are administered to patients, an appropriatedosage form is selected from tablets, capsule agents, powders, granules,ointments, injections, syrups and the like. In pharmaceuticalpreparations, various ideas are carried out corresponding to each dosageform. For example, percutaneous administration is known as one of theroutes of administration to patients to whom chemicals can be orallyadministered with difficulty. In general, a medicament which is a salthas inferior penetrability into the skin; therefore medicaments arefrequently made into a free form to formulate these drugs inpercutaneous pharmaceuticals.

However, the stability of a medicament differs depending on the state ofthe medicament such as a salt state and a free state. The state of themedicament sometimes causes a hindrance to pharmaceutical preparations.There is the case where antidementia medicament, particularly, donepezilbecomes unstable to light and/or heat when it is prepared and henceattention must be paid. In view of this situation, the inventors of thepresent invention have conducted intensive studies to increase thestability to light and/or heat and, as a result, found that the subjectcan be solved by the following means and completed the presentinvention.

DISCLOSURE OF THE INVENTION

The present invention is a stabilized composition of an antidementiamedicament comprising an antidementia medicament and an organic acid.The present invention is a method of stabilizing an antidementiamedicament by adding an organic acid to an antidementia medicament.

Specific examples of the antidementia medicament of the presentinvention include donepezil, TAK-147, CP118954 revastigmine,metrifonate, galanthamine and the like. Donepezil is generally used inthe form of donepezil hydrochloride, as a therapeutic agent forAlzheimer's disease from slight to middle degrees. Chemical name thereofis 1-benzyl-4-(5,6-dimethoxyindanone-2-yl)methylpyperidine. Chemicalnames of TAK-147 and CP118954 are3-[1-(phenylmethyl)pyperidine-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepine-8-yl)-1-propanefumarate, and5,7-dihydro-3-[2-[1-(phenylmethyl)-4-pyperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazole-6-onemaleate, respectively. The structural formulae of these compounds are asfollows.

No particular limitation is imposed on the organic acid used in thepresent invention. The examples thereof include higher fatty acid suchas tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaricacid, citric acid, fumaric acid, maleic acid and stearic acid.Particularly, mesyllic acid, salicylic acid and citric acid arepreferable. The organic acids may be used singly or by mixing two ormore. Citric acid has a particularly excellent effect on the heatstability of donepezil.

The organic acid may be added in an amount of 0.1 to 10 parts by weightto 1 part by weight of the antidementia medicament. The amount of theorganic acid is preferably 0.2 to 5 parts by weight and more preferably0.2 to 2 parts by weight.

Although no particular limitation is imposed on the ratio of donepezilto the organic acid, the amount of the organic acid is usually 0.1 to 10parts by weight, preferably 0.2 to 5 parts by weight and more preferably0.2 to 2 parts by weight to 1 part by weight of donepezil.

The composition of the present invention may be used in a form such astablets, granules, powders, ointments, injections or syrups. Each formis produced by a conventionally known method. For example, the granulescan be produced as follows: the antidementia medicament is mixed withfillers such as lactose, mannitol, corn starch and crystal cellulose, abinder such as hydroxypropyl cellulose and polyvinylpyrrolidonedissolved in a solvent such as water is added thereto, mixed, kneadedand then granulated using an extrusion granulator. The ointments can beused together with the so-called ointment bases such as liquid paraffin,hydrogenated oil, vegetable oil, squalene, higher alcohols, higher fattyacid, esters of higher fatty acid, glycerol, water, antiseptics anddyes, and may be produced by a usually used method.

Syrups are prepared by dissolving the antidementia medicament togetherwith sweetener such as sucrose, xylitol, mannitol and glucose in water.Further, a flavoring agent such as vanilla essence may be added ifnecessary.

According to the present invention, the stability of donepezil issignificantly increased. The effects of the present invention will beshown by way of concrete examples.

STABILIZATION TEST EXAMPLES

An ethanol/water (1/1) solution containing 1 mg/ml of donepezil wasprepared. Tosyllic acid, mesyllic acid, benzoic acid, salicylic acid,tartaric acid and citric acid are respectively added to the solution inamount by mol equivalent to donepezil. 5 ml of each resulting solutionwas sealed in a transparent glass ample. The pH of each resultingsolution was 5.74, 5.84, 5.73, 5.89, 5.75 and 3.28. The pH of thesolution in the case of adding no organic acid was 5.63. Each glassample was stored at room temperature under 1000 Lux for one month tomeasure the content. While each same solution was separately stored at acold place for a month and the content was measured to determine theresidual ratio under illumination of light. The content was measured byusing high performance liquid chromatography. The results are shown inTable 1.

TABLE 1 Organic Storage Outward Peak Residual acid condition appearancehight ratio (%) not added cold place − 41367 100.0 121° C., 20 min −42946 103.8 1000 Lux, 1 month ++ 35139 84.9 tosyllic acid cold place −42967 100.0 121° C., 20 min − 44320 103.2 1000 Lux, 1 month + 41856 97.4mesyllic acid cold place − 43386 100.0 121° C., 20 min ± 44202 101.91000 Lux, 1 month − 43164 99.5 benzoic acid cold place − 42667 100.0121° C., 20 min − 43547 102.1 1000 Lux, 1 month ++ 38813 91.0 salicylicacid cold place − 43075 100.0 121° C., 20 min − 43814 101.7 1000 Lux, 1month + 43326 100.6 tartaric acid cold place − 44598 100.0 121° C., 20min − 43284 97.1 1000 Lux, 1 month − 42926 96.3 citric acid cold place −42583 100.0 121° C., 20 min − 43102 101.2 1000 Lux, 1 month − 42346 99.4

As shown in Table 1, the composition according to the present inventionwas improved in light stability more significantly than the samples towhich nothing was added. The compositions containing each of,particularly, mesyllic acid, salicylic acid and citric acid wereconsidered to be not almost decomposed since no peak of the decomposedmaterials was observed on a chromatogram.

Because percutaneous pharmaceuticals such as ointments are frequentlyexposed to light after they are applied to the skin, the compositionaccording to the present invention is particularly useful.

Next, each of citric acid and maleic acid and as a control, hydrochloricacid and phosphoric acid was added to a 5 mg/5 ml donepezil solution inan amount shown in Table 2 and each resulting solution was stored at 60°C. for one month to measure the content. The pH was adjusted to 3.75.The results are shown in Table 2.

TABLE 2 The ratio of the area of Organic acid impurities on achromatogram (%) Citric acid 0.22 mg 0.07 15 mg 0.09 30 mg 0.10 45 mg0.10 malic acid 15 mg 0.10 Control hydrochloric acid 5 mg 0.42phosphoric acid 15 mg 0.43

Further, each of citric acid and as a control, hydrochloric acid wasadded to a 5 mg/5 ml donepezil solution containing 10% ofpolyvinylpyrrolidone (PVP) in an amount shown in Table 3 and eachresulting solution was stored at 60° C. for one month to measure thecontent. The results are shown in Table 3.

TABLE 3 The ratio of the area of Organic acid impurities on achromatogram (%) Citric acid 15 mg 1.34 45 mg 1.26 Control hydrochloricacid 5 mg 2.45

It is clear from Tables 2 and 3 that the composition of the presentinvention is reduced in the ratio of the area of impurities on achromatogram of high performance liquid chromatography moresignificantly than the control sample and is increased in stability alsoto heat.

EXAMPLES

The present invention will be hereinafter described in more detail byreferring to Examples, however the present invention is not limited bythem.

Example 1

5 g of donepezil, 5 g of tosyllic acid, 150 g of lactose, 200 g ofmannitol and 20 g of low-substituted hydroxypropyl cellulose were mixed.To the mixture was gradually added 7 g of hydroxypropyl cellulosedissolved in 50 ml of water, which was then mixed and kneaded. Thekneaded mixture was charged into an extrusion granulator to produce agranule. The screen was designed to be 0.4 mm.

Example 2

500 mg of donepezil, 200 mg of citric acid and 2000 mg of glucose weredissolved in water for injection. The pH of the solution was adjusted to5.5 by adding 0.1N sodium hydroxide. Then, water for injection wasfurther added to the solution such that the volume was 100 ml. Each 1 mlof the resulting solution was pipetted into an ample. The ample wasmelt-closed and then sterilized at 121° C. for 15 minutes to produce aninjection.

Example 3

100 mg of donepezil, 300 mg of sodium saccharate and 50 mg of citricacid were dissolved in 50 ml purified water. The pH of the solution wasadjusted to 5.5 by adding 0.1N sodium hydroxide. Then, 300 mg of methylparabene and 20 mg of propyl parabene which were dissolved in a smallamount of propylene glycol were added thereto. Purified water wasfurther added such that the total volume of the resulting solution was100 ml to produce a syrup.

What is claimed is:
 1. An antidementia medicament composition,comprising: an antidementia medicament and an organic acid, wherein theantidementia medicament is donepezil and the organic acid is selectedfrom the group consisting of tosyllic acid, mesyllic acid, benzoic acid,salicylic acid, tartaric acid, citric acid and combinations thereof,wherein the organic acid is not added to form a salt.
 2. The compositionas claimed in claim 1, which is stabilized to light and/or heat.
 3. Amethod for stabilizing an antidementia medicament, which comprises thestep of: adding an organic acid to an antidementia medicament, whereinthe antidementia medicament is donepezil and the organic acid isselected from the group consisting of tosyllic acid, mesyllic acid,benzoic acid, salicylic acid, tartaric acid, citric acid andcombinations thereof, wherein the organic acid is not added to form asalt.
 4. The method as claimed in claim 3, which comprises the step ofstabilizing to light and/or heat.
 5. The method as claimed in claim 3,wherein the organic acid is added in an amount of 0.1 to 10 parts byweight to 1 part of the antidementia medicament.
 6. The antidementiamedicament composition according to claim 1, wherein the amount oforganic acid is 0.1 to 10 parts by weight to 1 part by weight ofdonepezil.
 7. The antidementia medicament composition according to claim1, wherein the amount of organic acid is 0.2 to 5 parts by weight to 1part by weight of donepezil.
 8. The antidementia medicament compositionaccording to claim 1, wherein the amount of organic acid is 0.2 to 2parts by weight to 1 part by weight of donepezil.
 9. The method forstabilizing an antidementia medicament according to claim 3, wherein theamount added of organic acid is 0.2 to 5 parts by weight to 1 part byweight of donepezil.
 10. The method for stabilizing an antidementiamedicament according to claim 3, wherein the amount added of organicacid is 0.2 to 2 parts by weight to 1 part by weight of donepezil.